PROJECT SUMMARY Extraordinarily high rates of chronic kidney disease have been observed on the Pacific coast of several Central American countries including Nicaragua, El Salvador, Honduras, Guatemala, Costa Rica, and Southern Mexico. This increasingly recognized epidemic of kidney disease, known as Mesoamerican Nephropathy (MeN), is not associated with traditional risk factors such as diabetes or hypertension, and affects predominately young men who work in agriculture. Environmental factors such as heat stress, pesticides, infectious diseases, and many others have been proposed as potential explanations, but no clear cause has emerged. The postulated risk factors do not appear to be unique to the affected region, and they do not explain why some agricultural workers get kidney disease while others do not. We propose that genetic susceptibility is a major contributor to MeN risk, a hypothesis that we have strengthened by documenting striking familial clustering of disease. We have built strong relationships with local physicians, workers' groups, industry, and government in a MeN hotspot in Nicaragua. We have also built an interdisciplinary team with expertise in nephrology, genetics, epidemiology, and statistics. We have successfully enrolled nearly 1400 participants in our studies and performed preliminary genetic analyses that strongly support a significant genetic susceptibility to MeN, including identification of one set of genetic variants associated with MeN at genome-wide significance levels. We propose to 1) conduct a case-control genome-wide association study of former sugar cane workers with MeN and current healthy workers, 2) study 40 large, multigenerational MeN kindreds using a family-based genetic approach, and 3) validate our findings and conduct additional SNP discovery in a longitudinal community-based cohort, as well as in miners and brick makers who are also affected by MeN. Our study design is optimized to identify genetic risk variants with different combinations of frequency, effect size, and dependence on environmental interactions. This project will illuminate genetic risk factors that cause susceptibility to kidney disease in people of mixed ancestry in our Central American neighbors and may also help us understand mechanisms that contribute to high rates of kidney disease in other populations with Native American or Hispanic ancestry.